Immune function declines with age, resulting in increased susceptibility of aged individuals to infection and impaired responses to vaccines. The ability to generate T cell responses to newly encountered antigens and to respond to vaccination is dependent on the maintenance of a diverse repertoire of T cells. Aging is associated with reduced repertoire diversity in both mouse and human. We have previously shown that there is an age-associated reduction in repertoire diversity among naive CDS T cells, and using the mouse influenza virus model have defined profound consequences of reduced repertoire for primary and protective immunity of aged mice to influenza virus. We have new preliminary data showing that repertoire perturbations also impact CD4 T cell responses to influenza virus epitopes. Because of reduction of the naive repertoire in aged individuals, we hypothesize that aging results in a greater contribution of fortuitously cross-reactive memory cells to the response to new infections, and that this will lead to stochastic responses in individuals, often of lower avidity. In support of this, we have preliminary data showing that fortuitously cross-reactive memory cells from influenza-naive aged mice can respond to influenza virus epitopes, and in Aim 1 we will determine the contribution of cross reactive memory to the response to new infections, and the implications for cellular immunity. In Aim 2 we will focus on experimental interventions to enhance diversity of the T cell repertoire and protective immunity in aged mice. In the context of other projects in the Program, these studies will address mechanisms underiying the age-associated decline in cellular immunity which is essential for the goal of designing better therapies and vaccines for the elderiy. RELEVANCE (See instructions): Relevance: Our ability to respond to infection or vaccination decreases dramatically as we age. Elderiy individuals are significantly more susceptible to infections than the young, and respiratory infections, such as those caused by influenza virus, are a major cause of death and hospitalization in this group. Vaccines are therefore essential but, unfortunately, the elderiy are also more difficult to vaccinate. The studies proposed will determine the mechanisms underiying decreased immunity of the elderly, and will begin to test ways of overcoming these deficiencies in order to design better vaccines.